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The progression of preterm infant gut microbiome development is intricately linked with the development of the infant, such that disruptions to the microbial system can manifest as neonatal necrotizing enterocolitis (NEC) in the infant. One of the proposed aetiologies of NEC is that disease onset occurs when microbiome development is challenged by an external perturbation, such as antibiotic treatment. The research conducted in this thesis was motivated by the overarching hypothesis that infant health occurs when homeostatic microbial relationships have been established. Conversely, when microbiome development is disrupted, the preterm infant is susceptible to diseases such as NEC. Therefore, the driving hypothesis of this thesis was that external factors, such as antibiotic therapy or formula milk, impair microbial interactions such that the preterm gut microbiome no longer sustains healthy infant development, leading to NEC onset. This hypothesis was tested using fecal microbiota from two preterm infants with different antibiotic exposures while in hospital. Propagation of these preterm fecal microbiota in an in vitro continuous culture system allowed for compositional, metabonomic, culture-based annotation of the ecosystems. Longitudinal analysis of each community revealed differences in each community’s functional capacity. The Infant 1 community, which was antibiotic-naïve, was able to restore that same steady-state by 1-2 weeks after antibiotic treatment ended. In contrast, the Infant 2 community (had prior exposure to antibiotics) was not able to re-gain the same compositional state after antibiotic treatment, nor was it able to carry out similar secondary metabolisms. The differences in the two community’s resilience to in vitro antibiotic treatment was attributed to the microbial-microbial relationships in the in vitro communities. This work demonstrated that parenteral antibiotic therapy has the potential to disrupt microbe-microbe relationships such that the microbiome is hindered in its ability to function as a cohesive ecosystem. This work, which includes several other studies focused on examining the metabolic capacity of the early gut microbiome, provides groundwork that potentiates development of therapy alternatives that target endogenous microbial relationships to steer the preterm gut ecosystem towards a state of health. |
